Electroconvulsive therapy (ECT) remains the gold-standard treatment for severe, treatment-resistant patients with depressive episodes. During a typical 4-week ECT series, most depressive episodes remit, and formerly suicidal or psychotically depressed patients will resume their premorbid levels of functioning. ECT is one of psychiatry's most invasive treatments and remains limited to academic medical centers or larger, metropolitan hospitals. Despite ECT's 80-year history, the lack of understanding regarding the neurobiology and the mechanism of action of ECT response limit the development of safer, more accessible treatments. The overall aim of this investigation is to identify the biomarkers of ECT response. A case-control longitudinal design and resting state functional magnetic resonance imaging (fMRI) will simultaneously assess between (Aim 1) and within network changes (Aim 2) associated with ECT response. Our preliminary data supports our hypothesis that ECT response increases between network relationships amid frontal and default mode networks and reduces within network low frequency power (0.01 to 0.1 hertz (Hz)) in the subcallosal cingulate gyrus. The ECT series is associated with increased seizure threshold and reduced seizure duration. These anticonvulsant properties of ECT may be related to the reduction in spectral power within functional networks. In Aim 3, proton spectroscopy (H-MRS) will measure changes in concentrations of gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter, associated with ECT response. The multi-modal aspect of this investigation will link changes in GABA concentrations with changes in the fMRI biomarkers of ECT response (Aims 1 and 2). Specifically, we hypothesize that increased GABA concentrations in the posterior cingulate will correlate with reduced low frequency spectral power (0.01 and 0.1 Hz) within limbic and para-limbic networks. This research will impact the field with a better understanding of the functional neural correlates of ECT response, which will help to optimize ECT treatment parameters (e.g., pulse width, stimulus delivery method, number of treatments) and extend to other therapeutic interventions for treatment-resistant depression.